Part 2 book “Pesticide toxicology and international regulation” has contents: Toxicology of herbicides, microbial pesticides, biocides, variability of residues in unprocessed food items and its impact on consumer risk assessment, occupational aspects of pesticide toxicity in humans, treatment of pesticide poisoning,… and other contents.
Pesticide Toxicology and International Regulation Edited by Timothy C Marrs and Bryan Ballantyne Copyright 2004 John Wiley & Sons, Ltd.TISBN: 0-471-49644-8 Toxicology of Herbicidesà Timothy C Marrs Herbicides Herbicides are substances that kill plants They have variable degrees of specificity Some, for example paraquat, kill all green plants, whereas others, for example the phenoxy compounds, are specific for certain groups of plants A chemical classification is given in Table 7.1 These compounds, particularly the non-selective examples, are less likely to appear in food than insecticides and fungicides as they are less likely to be used on crops, but exposure of operators can occur as with other pesticides Inorganic herbicides Substances such as common salt (sodium chloride) have been used as herbicides for many years Indeed, the Romans are reputed to have sterilized the soil of Carthage with salt after the Romans’ victory in the third Punic war in 146 BC The disadvantage with such herbicides, from the agricultural point of view, is that they are non-selective Nevertheless, sodium chlorate continues to be used as a herbicide and when ingested in man it produces vomiting and abdominal pain, diarrhoea, methaemoglobinaemia, and intravascular haemolysis (Helliwell and Nunn, 1979; Proudfoot, 1996) Sodium chlorate is an oxidizing agent and poses a fire hazard (Pesticide Manual, 1991) Bipyridylium herbicides This group of pesticides contains two well-known non-selective herbicidal compounds, namely paraquat and diquat (Figure 7.1) In experimental animals and in humans, the mechanism of toxic action of both compounds is very similar at the à The views expressed in this chapter are those of the author and not necessarily reflect the views of any UK Government Department or Agency 306 TOXICOLOGY OF HERBICIDES Table 7.1 Main groups of herbicidesa Group Examples Inorganic Bipyridylium Organic acid Sodium chlorate Parquat Diquat 2,4-D 2,4,5-T Mecoprop Fenoprop Haloxyfop Dicamba Alachlor Propachlor Propanil Diuron Linuron Monolinuron Ioxynil Bromoxynil Atrazine Simazine Cyanazine Amitrole Glyphosate Glufosinate Phenoxy Other organic acids Substituted anilines Ureas and thioureas Nitriles Triazines and triazoles Triazines Organophosphate group Triazoles Phosphonic acid derivatives Phosphinic acid derivatives a Reproduced from Marrs and Dewhurst (1999), with permission of the authors and Macmillan Reference Ltd Figure 7.1 Bipyridilium herbicides molecular level and involves cyclic reduction – oxidation reactions which produce reactive oxygen species and depletion of NADPH However, the critical target organ differs with the two compounds, so that the mammalian toxicology is quite BIPYRIDYLIUM HERBICIDES 307 different While both herbicides affect the kidneys, paraquat is selectively taken up in the lungs and the toxicity of paraquat is dominated by lung toxicity Both can produce local contact toxicity Paraquat Chemical identification Class: bipyridilium herbicide Molecular weight: 186.3 (ion), 257.2 (dichloride) Common name: paraquat IUPAC name: 1,1-dimethyl-4,4-bipyridinium CAS name: 1,1-dimethyl-4,4-bipyridinium Synonyms: methyl viologen CAS no.: 4685-14-7 (ion) 1910-42-5 (dichloride) Paraquat is capable of producing both local and systemic toxicity Local toxicity is produced by direct injury to tissues with which the pesticide comes into contact Tissues commonly damaged in this way include the skin, the cornea, the larynx, and the mucosa of the upper gastrointestinal tract, the extent and severity of such damage being dependent on the concentration of paraquat in the formulation rather than the dose Because of the nature of the toxicity of paraquat, this substance is dealt with in more detail than some other herbicides discussed in this chapter As discussed above, the systemic toxicity of paraquat is dominated by pulmonary toxicity, which is the result of the active uptake of the compound by the lungs by a saturable uptake process (Rose, Smith, and Wyatt, 1974; Rose et al., 1976; Smith, 1982; Smith et al., 1990) Secondary target organs of toxicity are the kidneys and liver Absorption, distribution, and excretion Dey et al (1990) studied the pharmacokinetics of 14C-paraquat administered to rats as a single sc injection The dose was such as to produce lung damage but avoid kidney damage Paraquat was rapidly absorbed with peak blood concentrations at 20 The pharmacokinetics were best characterized as a two-compartment open model, the mean t1=2 being approximately 40 h Peak tissue concentrations in the kidney and lung were at 40 Hawksworth, Bennett, and Davies (1981) studied the elimination of paraquat in dogs After intravenous injection of low doses of 14C paraquat, label was rapidly excreted in the urine, the clearance being greater than the glomerular flitration rate, suggesting a process of active secretion Secretion could be inhibited by N0 -nicotinamide Large doses of paraquat (20 mg=kg bw) produced renal failure as evidenced by a decrease in both renal creatinine and paraquat clearance The elimination of paraquat could be described by a threecompartment open model 308 TOXICOLOGY OF HERBICIDES Mechanism of uptake in the lung A considerable amount of work has been done on the mechanisms that underly the toxicity of paraquat, and the fact that paraquat is concentrated by the lungs has been discussed above Rose et al (1976) showed that lung slices from rats, dogs, rabbits, and cynomolgus monkeys could concentrate paraquat actively Paraquat and the structurally similar polyamines, such as putrescine and spermidine, are accumulated by type II alveolar cells by the polyamine active uptake system (see review by Smith, 1985) Diquat is not a substrate for this system and this fact accounts for the different organspecific toxicity of the two bipyridilium compounds Chen, Bowles, and Pond (1992) studied the uptake kinetics of paraquat and putrescine and their mutual inhibition in rat type II alveolar cell suspensions The uptake of paraquat by type II cells exhibited saturation kinetics and could be inhibited in a concentration-dependent manner by putrescine The authors postulated that the polyamine uptake pathway in type II cells for paraquat and putrescine possessed two separate sites, one for each substrate, and that binding at one site leads to a conformational change in the other Uptake into the brain A number of investigators have looked specifically at entry of paraquat into the central nervous system, as a result of the suggestion that paraquat may be a factor in the aetiology of Parkinson’s disease (see below) Naylor et al (1995) examined the distribution of paraquat in the brain following subcutaneous administration of 14Clabelled paraquat to rats Following administration, label reached a maximal concentration in the brain (0.05 per cent of the administered dose) within the first hour and then rapidly disappeared from the brain However, 24 h after administration of the herbicide, about 13 per cent of the maximal recorded concentration of paraquat still remained in the brain and could not be removed by intracardiac perfusion Most of the paraquat was associated with five structures, two of which (the pineal gland and linings of the cerebral ventricles) lie outside the blood–brain barrier The remaining three brain areas, the anterior portion of the olfactory bulb, hypothalamus, and area postrema, not have a blood–brain barrier The authors concluded that paraquat remaining in the brain 24 h after systemic administration was associated with elements of the cerebral circulatory system, such as the endothelial cells that make up the capillary network, and also that there was limited entry of paraquat into brain regions without a blood–brain barrier Widdowson et al (1996a) compared the extent of paraquat entry into the brain of neonatal (10day-old), adult (3-month-old), and elderly (18-month-old) rats A single dose was administered sc, labelled with 14C-paraquat The rats were killed 30 or 24 h after injection, blood taken by cardiac puncture, and the brains removed Groups of neonatal, adult, or elderly rats were similarly injected and killed 24 or 48 h after dosing, for histopathological examination of the brain In all three groups, plasma paraquat concentrations were much higher at 30 than at 24 h At 30 the BIPYRIDYLIUM HERBICIDES 309 concentration of paraquat in the brain was highest in the elderly rats, while at 24 h the concentration in the adult and elderly rats’ brains had fallen, but it remained high in the brains of the neonatal rats Autoradiography showed similar distributions of paraquat in the brain regions, paraquat being found in areas outside the blood–brain barrier or where the barrier is incomplete, e.g dorsal hypothalamus, area postrema, and anterior olfactory bulb There was no evidence of paraquatinduced cell damage in neonatal brain, although there was increased paraquat entry in that group compared with the older rats Widdowson et al (1996b) studied the entry of paraquat into the brains of rats Paraquat labelled with 14C was administered orally, daily for 14 days to five rats while a further five rats received a single oral dose of mg ion=kg bw=day, labelled with 14C The rats were killed 24 h after the last of the 14 doses or after the single dose Brain paraquat concentrations were 10 times higher in those rats receiving multiple injections than in those receiving single doses Shimizu et al (2001) studied rats using a brain microanalysis technique with HPLC=UV detection and found that paraquat (5, 10, or 20 mg=kg bw sc) appeared in the dialysate of the striatum They also found that paraquat did not facilitate penetration of the blood–brain barrier by 1,2,3,6-tetrahydropyridinium ion L-Valine injection 30 before paraquat reduced the striatal extracellular paraquat concentrations The authors hypothesized that paraquat was taken up into the brain via the neutral amino acid transporter Metabolism Only a small fraction of orally-administered paraquat is metabolized, the greater part being excreted in the urine unchanged Daniel and Cage (1966) undertook a study in rats using 14C-labelled paraquat dichloride, and some evidence of metabolism was found Of the oral dose of paraquat, 30 per cent of the label was present in the gut as metabolic products Furthermore, a small amount of metabolite was present in the urine after oral but not sc administration, suggesting the absorption of metabolites from the gut Studies in vitro, using fecal homogenates, suggested that microbiological metabolism was responsible for this In a gavage study reported by Murray and Gibson (1974) in rats, guinea pigs, and monkeys, using 14C-labelled paraquat, metabolites were not observed The metabolism that does occur is via demethylation and oxidation Animal toxicology In experimental animals, the toxicity of paraquat is dominated by effects on the lungs and, to a lesser extent, the kidney Brooks (1971) carried out studies on small groups of mice exposed to 50–300 ppm in their drinking water and retained for from to 16 weeks The main findings on light microscopy were vascular dilatation and veins filled with platelets and eryrthocyte aggregates At the higher doses interalveolar septal thickening was seen At 100 ppm and above, focal or sometimes lobar pneumonitis 310 TOXICOLOGY OF HERBICIDES was observed, with small mononuclear cells, macrophages, and neutrophils In those mice receiving paraquat for weeks or more, fibroblasts were seen in the septal walls Obliteration of air spaces was seen The type II cells were observed to be undamaged on electron microscopy in this study, but the type I cells were swollen and there was evidence of oedema of interalveolar septa The alveolar air spaces were filled with a clear exudate and where there was consolidation, fibroblasts and collagen were observed Lymphocytes and plasma cells were noted Subsequent studies have shown damage to other cell types such as the type II alveolar cells and clara cells (see FAO=WHO, 1987) In other species, such as the rat, dog, and monkey, the histopathological appearances are generally similar to those in mice (Clark, McElligott, and Hurst, 1966; Murray and Gibson, 1972), although Butler (1975) found the Syrian hamster relatively resistent to interstitial fibrosis Butler and Kleinerman (1971) reported that rabbits did not develop the pulmonary changes typical of paraquat poisoning in other species, despite doses of 2–100 mg=kg bw being administered ip and sacrifice of animals being delayed up to month The only findings in the lungs were occasional small interstitial infiltrates of lymphocytes and plasma cells, minimal alveolar hyperplasia, and some alveolar macrophages In regulatory studies the changes seen mainly reflect the pneumotoxicity of paraquat Thus, in short-term studies in rodents and dogs, lung changes occurred: these were also seen in a 1-year dog study Effects may also be observed in the gastrointestinal tract, the liver, and in the blood Long-term toxicity including carcinogenicity Paraquat is not considered to be carcinogenic; however, in some long-term studies lung tumours have been observed (FAO=WHO, 1987) As with diquat (see below) cataracts have been observed in rats Developmental and reproductive toxicity Neither specific reproductive toxicity nor teratogenicity has been observed except where accompanied by maternal toxicity (see also FAO=WHO, 1987; WHO, 1984) In a study by Bus et al (1975) in mice, no teratogenic effect was observed, although a slight degree of non-ossification of sternabrae was seen at all test doses Fetotoxicity, as evidenced by increased percent resorption, was seen only at the higher of the two doses used At no dose was the number of fetuses, or their mean body weight, affected by treatment Radioactivity reaching the mouse embryo, when 14C-labelled paraquat was administered orally on day 11 of gestation, was low The developmental toxicity of paraquat was determined in rats by administering paraquat iv at a single dose of 15 mg=kg bw on a single day, one of the days 7–21 of gestation The number of live and dead fetuses and resorptions was counted at day 22 (or before for decedent dams) Excess maternal deaths occurred with paraquat compared with the saline controls and there was an increase in the number of dead and resorbed fetuses BIPYRIDYLIUM HERBICIDES 311 Bus and Gibson (1975) administered paraquat in the drinking water at 50 or 100 ppm to mice, exposure starting at day of gestation and continuing until 42 days post partum Neither treatment altered the post-natal growth rate nor did drinking water at 50 ppm increase the post-natal mortality Drinking water containing paraquat at 100 ppm increased the post-natal mortality, and increased the sensitivity of pups to oxygen toxicity and 28 days after birth, whereas 50 ppm paraquat in the drinking water did not Both concentrations of paraquat in the drinking water increased the sensitivity to oxygen toxicity and to bromobenzene at 42 days after birth The authors considered that the effect of bromobenzene might be due to depletion of reduced glutathion A two-generation study of the reproductive toxicity of paraquat was undertaken by Dial and Dial (1987) Exposure of the parental (F0) mice continued until the weaning of the F1 mice, which were exposed to the diet for 49 days post-natally No differences were observed in the females’ age at first parturition, pups borne=litter, or in pup abnormalities; however, at the highest dietary concentrations the number of pairs of mice producing litters was reduced on account of maternal deaths Furthermore, the highest dietary concentration produced effects on F1 offspring mortality The F1 females’ age at second parturition was increased and the F2 mortality at weeks was increased Excess mortality was not observed in the F1 parents Maternal and offspring lungs were histopathologically abnormal, with extensive fibrosis Production of cell damage Bus, Aust, and Gibson (1976) studied the hypothesis that the pulmonary toxicity of paraquat is due to cyclic reduction–oxidation, with generation of superoxide radicals and singlet oxygen with the production of lipid peroxidation Mouse lung microsomes in vitro catalysed NADPH-dependent reduction of paraquat Incubation of paraquat with NADPH, NADPH-cytochrome reductase, and purified microsomal lipid increased malondialdehyde production Addition of superoxide dismutase or 1,3-diphenylisobenzofuran (a singlet oxygen trapper) inhibited paraquat-induced lipid peroxidation Paraquat toxicity in mice was decreased by phenobarbital and increased by selenium, vitamin E, or reduced glutathion deficiency Paraquat toxicity was increased by exposure to 100 per cent oxygen Genotoxicity It is difficult to summarize the data on the genotoxicity of paraquat because of the large number of tests that have been done, the discrepant results, and the nonstandard systems used In many cases the purity of the material was not stated and studies have not been to Good Laboratory Practice (GLP) standards The majority of Ames tests undertaken on paraquat have been negative (e.g Benigni et al., 1979; Eisenbeis, Lynch, and Hampel, 1981; Moriya et al., 1983; Nishimura, Nishimura, and Oshima, 1982; Shirasu et al., 1982) or weakly or marginally 312 TOXICOLOGY OF HERBICIDES positive (Lin, Kuo, and Hsu, 1988; Moody and Hassan, 1982) Of other studies in vitro a DNA-repair test in Salmonella typhimurium TA 1538 and TA 1978 was positive (Benigni et al., 1979) Of the studies in vivo, mouse micronucleus tests conducted by Prabakaran and Moorthy (1998), Melchiorri et al (1998) and Ortiz et al (2000) were all positive, whereas that reported by Pena, Mesquita, and Colus (1999) was negative Mouse dominant lethal tests reported by Pasi et al (1974) and Anderson, McGregor, and Purchase (1976) were negative Effects in humans Paraquat is a major cause of death from poisoning Casey and Vale (1994) tabulated deaths from pesticide poisoning from 1945 through 1989 in England and Wales: paraquat was responsible for 570 deaths, which was 56.3 per cent of all deaths caused by pesticides Paraquat poisoning usually is the result of ingestion of liquid paraquat formulations available to farmers and professional horticulturists Much less often, fatal paraquat poisoning may result from ingestion of preparations available for home garden use or from dermal absorption (Garnier et al., 1994; Papiris et al., 1995) There are numerous case reports and case series of paraquat poisoning (e.g Bismuth et al., 1982; Bramley and Hart, 1983; Bullivant, 1966; Campbell, 1968; Carson and Carson, 1976; Douze et al., 1974; Hall, 1995; Malone et al., 1971; Naito and Yamashita, 1987; Tsatsakis, Perakis, and Koumantakis, 1996; van Wendel de Joode et al., 1996; Wesseling, Castillo, and Elinder, 1993; Wesseling et al., 1997) The effects of paraquat are local and systemic, the former being concentrationdependent, while the latter are dose-dependent (Proudfoot, 1999a) Local effects include damage to the skin, nails, and nose (Bismuth, Hall, and Wong, 1995; Hearn and Keir, 1971; Samman and Johnston, 1969; Vale, Meredith, and Buckley, 1987) and sore throat, dysphagia, and epigastric pain may occur Local effects to the eye may heal only slowly and with scarring (Deveckova´, Mra´z, and Mydlik, 1980; Peyresblanques, 1969) Ulceration of the upper gastrointestinal tract is often observed Although the local effects can be severe and unpleasant, it is the systemic effects, largely referable to the respiratory system, that are potentially lethal Crepitations may be heard and there may be dyspnoea and cyanosis Radiology initially reveals diffuse fine mottling of the lungs Renal dysfunction may partly be a direct effect of paraquat and partly be caused by hypovolaemia Although the degree of renal failure may be mild by most standards, renal failure impairs the only route of excretion available and therefore may contribute significantly to the mortality produced by paraquat Lung function tests are commonly abnormal (Bismuth et al., 1982) The course of the poisoning depends on the amount of paraquat ingested Ingestion of large amounts (>6 g) of paraquat usually results in death within 36 h, acute pneumonitis, shock, metabolic acidosis, and convulsions commonly being seen Nausea, vomiting, and abdominal pain are also present After ingestion of BIPYRIDYLIUM HERBICIDES 313 smaller amounts (3–6 g) death is usually delayed for 5–10 days Respiratory distress becomes apparent after 4–7 days: radiologically there is opacification of the lungs and hypoxia which becomes increasingly severe as death approaches The ingestion of amounts of paraquat smaller than g, even as low as 1.5 g may produce death, although the lung effects are likely to be delayed, sometimes considerably so Initially, there may be nausea, vomiting, and abdominal discomfort together with mild renal impairment However, dyspnoea may occur after about 10–21 days, death from pulmonary fibrosis occurring up to weeks after exposure Paraquat concentrations in plasma taken within 24 h of exposure are predictive of the outcome in 90 per cent of cases (Proudfoot, 1995) Proudfoot et al (1979) reported that the plasma paraquat concentration was a good predictor of the outcome in that those whose concentrations were below 2.0, 0.6, 0.3, 0.16, and 0.1 mg=L at 4, 6, 10, 16, and 24 h after ingestion survived Scherrmann et al (1987) reported that plasma paraquat concentrations in those admitted more than 24 h after poisoning were predictive of the outcome of the poisoning in most patients Furthermore, they concluded on the basis of 53 patients that those with urinary concentrations of paraquat of less than mg=L within 24 h of exposure would survive, whereas a fatal outcome could be anticipated in most in whom the urinary concentration of paraquat was higher The appearence of the lungs at autopsy depends on the survival time There may be a pleural effusion, and damage to the upper respiratory tract Grossly, the lungs appear solid, with haemorrhages, including subpleural ones Histologically there is an initial destructive acute alveolitis, type I alveolar cells being the first cell type affected Later, type II alveolar cells are affected and clara cells may be destroyed There follows a proliferative phase, with fibroblastic proliferation in the alveolar walls Infiltration with mononuclear cells, polymorphs, macrophages, and eosinophils has been reported The alveoli show oedema and are airless (Marrs and Proudfoot, 2003) The longer the survival time the greater the proliferation of epithelium and fibroblasts in the alveoli (Carson and Carson, 1976) Tubular damage in the kidney has been reported as well as mid-zonal and centrilobular degeneration in the liver In a fatal case of paraquat poisoning in a pregnant woman, who developed the typical symptoms and signs of paraquat poisoning and, at post mortem, had the typical lung pathology of paraquat poisoning, the fetal lungs were normal (Fennelly, Gallagher, and Carroll, 1968) However, Talbot and Fu (1988), who reported the details of nine pregnant women who ingested paraquat, stated that paraquat in one case was concentrated 4–6 times in the fetus In another of the cases, the amniotic fluid contained paraquat at twice the concentration in the maternal blood All the fetuses died, whether or not Caesarian section was carried out Although most patients who have radiological lung changes go on to develop progressive and ultimately fatal lung damage, there are a few case reports in which patients have developed persistent radiological changes but have survived (e.g Hudson et al., 1991) There is also evidence that, in such patients, some recovery 314 TOXICOLOGY OF HERBICIDES may occur over time (Lin, Liu, and Leu, 1995; Ming, Chun, and Khoo, 1980; Papiris et al., 1995) The vast majority of paraquat intoxications are by ingestion However, Athanaselis et al (1983) reported the poisoning of a 64-year-old spray operator via the skin Fluid had leaked down his back for several hours, causing irritation of the skin Two days later the sprayman visited a doctor, who advised hospitalization The patient rejected this advice but was admitted days later into hospital He died 12 h after this of toxic shock and renal and respiratory insufficiency At autopsy the findings were typical of paraquat poisoning with fibrosing interstitial pneumonitis and intra-alveolar haemorrhage in the lungs, renal tubular cell degeneration, cholestasis, and necrosis of the skin of the back A further case of a fatality from transdermal exposure to paraquat was reported from Papua New Guinea, the patient evidently thinking that Gramoxone (20 per cent paraquat w=v), would kill lice, for which purpose he applied the material to his scalp and beard This produced painful sores and he steadily deteriorated until dying days after applying the paraquat to his skin At autopsy, there were skin lesions as well as solid and haemorrhagic lungs (Binns, 1976) Garnier et al (1994) reported two cases of percutaneous exposure In the first case a 36-year-old man applied 20 per cent concentrate to his whole body to cure scabies He developed extensive erythema followed by blistering and days later he was admitted to hospital He developed transient renal failure Dyspnoea appeared one week after admission and he deteriorated, dying 26 days after exposure The other case reported by Garnier et al (1994) was much milder with mainly skin effects and the outcome was not fatal Further cases of fatal percutaneous paraquat intoxication were reported by Newhouse, McEvoy, and Rosenthal (1978), Levin et al (1979), Wohlfahrt (1982), Okonek et al (1983), and Papiris et al (1995) In general systemic toxicity after percutaneous exposure of humans seems unusual (Hoffer and Taitelman, 1989) In the case of fatal cases arising from dermal absorption it is likely that the skin was abnormal Treatment There is no specific antidotal treatment for paraquat poisoning, although numerous measures have been tried, many concentrating on the prevention of absorption (Meredith and Vale, 1987) Gastric lavage, fullers’ earth, and activated charcoal have all been used Other therapies that have been investigated include removal of paraquat from the blood by forced diuresis, peritoneal dialysis, haemodialysis, or haemoperfusion using sorbent materials, including charcoal haemoperfusion (Tabei, Asano, and Hosoda, 1982) Corticosteroids have also been tried (Bismuth et al., 1982) as have acetylcysteine and deferoxamine (Lheureux et al., 1995), nitric oxide by inhalation (Eisenman et al., 1998), radiotherapy (Talbot and Barnes, 1988), and lung transplantation Some measures have at times seemed promising, thus Addo, Ramdial, and Poon-King (1984) reported that treatment with cyclophosphamade, dexamethasone, forced diuresis with frusemide, triamterine, and hydrochlorothiazide 530 THE REGULATORY SYSTEM IN JAPAN Establishment of maximum pesticide residue levels (MRLs) MRLs are estimated using data from field trials conducted according to GAP MRLs are ordinarily calculated on an individual crop basis, called the Food Standard, and issued by the MHLW However, when the TMDI exceeds the ADI, the MRL is calculated on crop group basis and called the Standard for Withholding Registration; this is issued by ME Often MRLs issued by the two Ministries are the same, but the ME may take account of environmental concerns as well as the GAP and hence the MRL may reflect this and differ from that of the MHLW The MHLW also estimates national TMDIs of pesticides (NTMDIs) in Japan using MRLs and food factors MRLs for a particular crop are estimated using the data from residue studies conducted under GAP (see above), and the food factor is the mean daily intake of the crop concerned These data are obtained from national nutritional surveys Intake of pesticide in drinking water is also included in the calculation of the NTMDI and allocated a maximum of 20 per cent International standards such as Codex MRLs have been largely accepted by virtue of the SPS agreement (SPS, 1994) However, national MRLs are also used as domestic MRLs for some crops produced in Japan The reason is that Japanese GAP may be unique in terms of post-harvesting uses, target pests, climate, method of pesticide treatment, and methods of cultivation Japanese farms are of small size and multiple types of cultivation are often undertaken at a single farm The estimated total dietary exposure is in fact thought to be much more than the real pesticide intake level The MHLW has been calculating national estimated maximum daily intake (N-EMDI) and supervised trials median residue levels (STMRLs) in trials since 1998, in the light of the Codex Committee on Pesticide Residues’ recommendations The N-EMDIs are estimated taking account of the proportion of commodities that are edible, processing and cooking, and other factors where appropriate The real dietary intake of pesticide residue is calculated based on the data from the National Market Basket Survey The MHLW calculates the total daily intake of each pesticide, according to the market basket studies Food groups, including drinking water, are divided to 14 classes Approximately 100 kinds of foods are collected and cooked by the procedure usually used in Japanese households The pesticide content in the cooked food is analysed The intake of the pesticide detected in food is allocated 20 per cent of the detectable limit to the food The total daily intake is estimated from the amount of the pesticide in the daily intake volume of each food Six pesticides were detected in foods from the results of market basket studies in 1995 and 1996 At the present time, N-EMDIs are used as reference values for ensuring safety of pesticide residues in food The Investigation Council on Pesticide Residues is convened at the request of the Department of Food Safety, and decides whether the recommendation on the ADI DATA REQUIREMENTS FOR REGISTRATION OF PESTICIDES IN JAPAN 531 can be adopted, based on a comparison with the TMDI or sometimes the EMDI estimated from MRLs The council recommends to the Food Sanitation Council that MRLs, which not cause exceedences of the TMDI or EMDI, should be the Food Standards (MHLW-MRLs [see above]) The Food Sanitation Council submits a report on the Food Standard and=or Standard for Withholding Registration, and other standards involved to the highest council, the Pharmaceutical Affairs and Food Sanitation Council Data requirements for registration of pesticides in Japan Newly produced or newly imported pesticides should be notified to the MAFF for risk assessment of safety in the use of the pesticide and risk assessment of likely residues in food The primary producer or the importer needs to submit the required data set to the MAFF The required data set comprises technical specification and chemical identity, proposed pattern of use (direction for use), residue chemistry in crops and the soil, environmental fate in crops, soil, and water, metabolism and toxicological studies, together with a toxicological evaluation The dossier is reviewed and evaluated for both safety in use and safety of human exposure to residues All the data described below are not always required The specification and chemical identity The specification will include the chemical and international standard name and code, empirical and structural formulae, physical and chemical properties of the active ingredient, the composition, including the nature of any impurities, the technical grade of the active ingredient, and the nature of co-formulants in the formulation Information on the stability of the formulated substance under different conditions is also mandatory Directions for use The data on directions for use of the pesticide include use pattern and application procedure, mechanism of action, nature of the target pests, biological efficacy and efficacy on the target pests (insects, weeds, or fungi), and the ecological effects of the pesticide These last will include information on potentially harmful effects on crops, beneficial insects, fish, birds, and other wild creatures Ecological data required may include toxicology tests on beneficial insects including LD50 or LC50 for the honeybee, silkworm and predators=parasites of vermin Environmental toxicology tests for avian species include LD50 for mandarin duck and=or quail (Coturnix coturnix) Data on 532 THE REGULATORY SYSTEM IN JAPAN environmental toxicology tests for aquatic organisms are usually data on LC50 for carp, Daphnia, other species such as loach (Cobitidae), crayfish (Canbarus), mullet, rainbow trout (Salmo gairdnerii), etc and data on fish accumulation Data on environmental toxicology tests for other beneficial animals (such as shellfish and earthworms) or plants (such as algae and surrounding plants) can be required, depending on the situation In addition to the above, a description of the analytical methods for the pesticide in biological matrices is also required Data on residue chemistry (residues in crop and soil) Residue chemistry data are used to estimate the exposure of the population to the pesticide residue in food and are the results of tests on the amount of residues remaining in food and soil, analysed according to the analytical methods supplied by the applicant for registration Information on the amount, frequency, and time of pesticide application are necessary to decide the directions for use of the pesticide Residue data (information on residue in crops and soil) in field and orchard application trials conducted under GAP provided by the MAFF are required Data on residues in target crops (including orchard crops and crops such as tea, etc.) or residues in crops that are cultivated adjacent to the treated crop are needed The residue data (including the nature and magnitude of the residue) from at least two supervised trials for each crop using a similar application method to the proposed method of agricultural use are required, together with the analytical method used Field trials are ordinarily conducted at a minimum of two separate laboratories belonging to national or local government agricultural experimental establishments Data on residues of pesticide in the soil are required to provide directions for use of the pesticide Dissipation studies need to be conducted using the samples collected from at least two different types of field (usually from upland and=or paddy fields) Either laboratory soil (in pots) or field soil can be used Environmental fate in crops and soil In Japan, about 60 per cent of agricultural chemicals are used in paddy fields (rice growing in water), while about 40 per cent is used in upland (fields used for growing crops such as wheat, maize, vegetables, or rice, not in water) Data on the environmental fate of the pesticide in crops and soil are required for evaluation of the risk of environmental pollution in food and to non-target species Information on the fate of the pesticide in plants should include data on absorption, mobility in plants, and major metabolic pathways including photo-reactions and analysis of metabolites Information on the fate of the pesticide in soils should include data on decomposition, mobility and absorption under aerobic and anaerobic conditions, and, in the case of pesticides susceptible to hydrolysis, the products of hydrolysis and photolysis in water CONCLUSION 533 Toxicological studies (Table 15.1) Data requirements in Japan have been revised in accordance with recent changes in the OECD requirements for toxicological, residue, and environmental data The major revision is the additional requirement for neurotoxicity studies The toxicological data base which is required for the assessment of the risk in human exposure to pesticide residues in food comprises acute oral toxicity studies, tests on irritation to skin and eye, and tests on skin sensitization Other tests that are required are oral neurotoxicity studies (acute and repeat study when some evidence is observed in acute or 90-day repeated oral toxicity studies) and 90-day repeat oral toxicity studies Long-term dietary toxicity studies (one year repeated dose toxicity study and carcinogenicity study or a toxicity=carcinogenicity combined study), reproductive toxicity studies (a two-generation study), and studies of developmental toxicity, a genotoxicity study, an animal metabolic study, and studies of physiological or pharmacological responses to the test chemical The carcinogenicity study will usually be of at least 18 months duration in mice and years or more in the rat An oral delayed neurotoxicity study (acute and 28day repeat when necessary), dermal toxicity studies (acute and 21-day repeat toxicity), and inhalation toxicity studies (90-day repeat toxicity) are required when a class of pesticide or type of exposure give rise to specific concerns about risks to human health All the oral toxicity studies and studies of acute exposure, including oral, dermal, and inhalation exposure, must be evaluated on the technical grade active ingredient(s) Formulated products are used in the evaluation of acute toxicity, irritancy, and sensitization Data on the acute oral toxicity of crop metabolites are required when the intake of the metabolite remaining in an edible portion of the crop gives rise to concerns about risks to human health General pharmacology (bio-function) studies Data on physiological or pharmacological responses to the pesticide are required for registration purposes The data can provide useful information to predict and characterize possible acute poisonings in humans and to provide information on first aid treatment for intoxication The studies comprise a detailed clinical observation and tests on pharmacological and toxicological effects of pesticide on major organ systems, such as the central nervous system, the respiratory system, the cardiovascular system, and the renal system Tests on the functions of other systems, e.g the autonomic nervous system, skeletal musculature, haematological system, gastrointestinal system may also be required if indicated Conclusion MHLW had established MRLs of 161 pesticides (138 in domestic use) in 130 kinds of crops by 1998 On the other hand, MRLs of 171 pesticides for 12 groups of crop, 534 THE REGULATORY SYSTEM IN JAPAN 78 pesticides for water and soil had been set as Standards for Withholding Registration by the ME before 1998 Thus pesticides are regulated by several standards according to their value in use, degree of exposure and risk assessment for humans, and the environment The MAFF has registered 309 pesticides, based on the risk assessments of pesticide described above under the Agricultural Chemicals Law (MAFF, 1948) The Standard for Direction of Use is applied to 109 pesticides for crops and pesticides for water Fifteen pesticides are designated as the objects of standards for quality of drinking water under the Drinking Water Law (MHLW, 1957) Sixteen pesticides are designated as the objects of the standard for water quality in the environment under the Basic Environment Law (ME, 1993) Eight pesticides are designated as objects of the Standards for Soil in Environment under Basic Environment Law Sixteen pesticides are regulated under the Water Pollution Protection Law (ME, 1970) Standards for Direction of Use are applied to 47 pesticides based on ecological effects, under the Basic Environment Law (ME, 1993) Some of these pesticides are also regulated by other standards or law (such as Poisonous and Deleterious Substance Law), and standards such as those for aerial spray or for pesticides used on golf courses; which standards apply depends on the pattern of use Pesticides thus are comprehensively regulated in Japan by several Ministries to ensure protection of public health and wildlife, and this is complex because of the variety of Japanese countryside in terms of climate and terrain Japan has small valleys and plains, short rivers, many high mountains and spreads over many degrees of latitude Furthermore, Japan is a densely populated country and many highly populated areas are contiguous to areas of food production Note: The MHLW has currently established MRLs for 229 pesticides (September 2003) References MAFF (1948) Ministry of Agriculture, Forestry and Fisheries: Agricultural Chemicals Law, Parliament Legislation Bureau no 82, Tokyo ME (1970) Ministry of the Environment: Water Pollution Prevention Law, Parliament Legislation Bureau no 138, Tokyo ME (1993) Ministry of the Environment: Basic Environment Law, Parliament Legislation Bureau no 91, Tokyo MHLW (1947) Ministry of Health, Labor and Welfare: The Food Sanitation Law, Parliament Legislation Bureau no 233, Tokyo MHLW (1957) Ministry of Health, Labor and Welfare: Drinking Water Law, Parliament Legislation Bureau no 177, Tokyo SPS (1994) Sanitary and phytosanitary agreement Final act of the General Agreement on Tariffs and Trade (Uruguay Round) Text available from the World Trade Organization, Geneva Pesticide Toxicology and International Regulation Edited by Timothy C Marrs and Bryan Ballantyne Copyright 2004 John Wiley & Sons, Ltd.TISBN: 0-471-49644-8 Index Abamectin, 161–163 structure, 161 Acceptable daily intake (ADI), 18, 64, 111, 114, 116, 147, 160, 424, 505, 519, 527, 528 Acceptable occupational exposure level (AOEL), 432–435 Acetylcholine, 89–95 Acetylcholinesterase (AChE), 8, 12, 13, 89, 114, 116, 147, 332, 435, 436, 442, 447, 477–479, 529 ageing, 103–106 biochemistry, 95 classification, 90, 91 effects of inhibition, 107, 108 inhibition, 89, 107 mechanisms of inhibition, 101–107 physiological function, 90, 91 reactivation, 103–106 structure, 91–94 ACGIH see American Conference of Governmental Industrial Hygienists AChE see acetylcholinesterase Acrolein (Acrylaldehyde), 274 chemistry, 274 lung injury, 277 mechanism of action, 275 toxicology, acute toxicity, 275 chronic toxicity, 275 developmental toxicity, 276 ecotoxicology, 278 genetic toxicology, 275 human toxicology, 277 metabolism, 277 occupational toxicology, 277 oncogenicity, 275 primary irritation, 275 reproductive toxicity, 276 subchronic toxicology, 275 toxicokinetics, 277 uses, 275 Acrylaldehyde see acrolein Actidione see cycloheximide ACTs see Advisory Committee on Toxic Substances Acute dietary exposure, 419–423 Acute toxicity, 10, 34, 41–43, 45, 53, 146, 165, 166, 171, 173, 179, 180, 181, 197, 198, 201, 202, 204, 206, 209, 214, 216, 218, 220, 221, 224, 226, 228, 230, 232, 234, 236, 238, 239, 241, 243, 248, 250–252, 254–256, 258, 259, 261–263, 265, 266, 269, 270, 272, 275, 280, 282, 321, 327, 331, 333, 351, 369, 374, 383, 387, 390, 418, 428, 445, 457, 504, 518, 529, 533 ADAC see n-Alkyl-n,n-dimethyl ammonium chloride ADI see acceptable daily intake Advisory Committee on Toxic Substances (ACTs), 14 Aggregate risk assessment, 523, 524 Alcohol dehydrogenase, 223 Aldicarb, 96 n-Alkyl-n,n-dimethyl ammonium chloride chemistry, 373 4-Alkyl-2,6-dimethyl morpholine see tridemorph Allergic contact dermatitis, 9, 197, 200, 206, 208, 215, 216, 221, 223, 225, 227, 230, 232, 244, 246, 372, 374, 393, 394, 400, 436, 437, 439, 453, 467 536 INDEX American Conference of Governmental Industrial Hygienists (ACGIH), 8, 14, 18, 433 2-Aminobenzimidazole, 233, 238 -Aminobutyric acid (GABA), receptors, 30, 35, 36, 62, 63, 138 4-Amino-2,6-dichloroaniline, 203 5-Amino[2,6-dichloro-4(trifluoromethyl) phenyl]-4-[(1R,S)-trifluromethylsulfinyl]-1H-pyrazole-3carbonitrile see Fipronil Amitrole, 458 Ampelomyces quisqualis, 353 Antibiotics, 1, 161, 165, 195, 279, 280, 355, 365, 367 Anticholinesterase, 13, 89, 95, 96, 114, 116, 147, 332, 435, 436, 442, 477–479, 529 Anticoagulants, 454, 486 Antidotes, 11, 104, 108, 110, 473, 476, 478, 479, 492 Aquatic toxicology, 16, 371 Arsenic, 489 treatment of poisoning, 489 Asthma, 394 Atropine, 11, 108–110, 442–444, 474, 476, 478, 479 Attractants, 185 Avermectins, 161, 162 absorption, 162 developmental toxicity, 162 distribution, 162 excretion, 162 human toxicology, 487, 488 metabolism, 162 reproductive toxicity, 162 toxicity, 162, 163 treatment of poisoning, 487–489 Avian toxicology, 16 Azadirachtin, 183 genetic toxicology, 184 human toxicology, 184 reference dose, 185 toxicology, 183, 184 Azoles, 4, 248 Bacillus subtilis, 280 Bacillus thuringiensis, 353–359 Bacteria, 1, 2, 159, 161, 351, 357, 365, 366, 369, 372, 373, 375, 376, 379, 385, 389, 516 BAL (British antilewisite) see dimercaprol Barium, treatment of poisoning, 491 BChE see butyrylcholinesterase Beauveria bassiana, 359 BEI see Biological exposure index Benomyl (Methyl 1-(butylcarbamoyl) benzimidazole-2-yl carbamate), 231 chemistry, 231 mechanism of action, 231 toxicology, acute toxicity, 232 chronic toxicity, 232 developmental toxicity, 232 ecotoxicology, 233 human toxicology, 233 metabolism, 233 occupational toxicology, 233 oncogenicity, 232 primary irritation, 232 reproductive toxicity, 233 sensitizing potential, 232 subchronic toxicity, 232 toxicokinetics, 233 uses, 231 Benzimidazoles, 4, 231 Benzodiazepine receptor, 138 Bioaccumulation, 16, 167, 174, 177, 207, 211, 377, 383 Biocides, 2, 3, 18, 300, 365–401, 501, 506, 508, 510, 511, 516 chemistry, 367 Biocides directive, 18 Bioconcentration, 208, 383 Biofilm, 367, 389 Biological exposure index (BEI), 6, 436, 446 Biological monitoring, 13, 433–436, 450–453, 522 Biomarkers of effect, 8, 13 Blasticidin-S, 279, 284 BNP see 2-Bromo-2-nitropropane-1,3-diol INDEX Bordeaux mixture, 2, 286 Boric acid, 481 British Standards Institute (BSI), 2-Bromo-2-nitropropane-1,3-diol, 375–377 chemistry, 375 decomposition, 376 mechanism of action, 375 toxicology, acute toxicity, 376 ecotoxicology, 377 metabolism, 377 primary irritation, 376 sensitization, 376 toxicokinetics, 377 uses, 336, 376 BSI see British Standards Institute N-tert-Butyl-N-(4-ethylbenzoyl)-3,5dimethylbenzohydrazide see Tebufenozide Butyrylcholinestease (BChE), 89, 111 Bystander risk assessment, 521, 522 Candida albicans, 379 Captafol, chemistry, 245 mechanism of action, 245 toxicology, acute toxicity, 246 chronic toxicity, 246 developmental toxicity, 246 ecotoxicology, 247 genetic toxicology, 246 human toxicology, 246 occupational toxicology, 246 oncogenicity, 246 primary irritation, 245 reproductive toxicity, 246 sensitizing potential, 246 uses, 245 Captan (N-(Trichloromethylthio)cyclohex4-ene-1,2-dicarboximide), 242 chemistry, 243 mechanism of action, 243 toxicology, acute toxicity, 243 chronic toxicity, 243 537 developmental toxicity, 244 ecotoxicology, 244 genetic toxicology, 244 human toxicology, 244 metabolism, 244 occupational toxicology, 244 oncogenicity, 243 primary irritation, 243 sensitizing potential, 243 subchronic toxicity, 243 toxicokinetics, 244 uses, 24 Carbamates, 4, 9, 13, 19, 96, 97, 101–103, 117, 194, 217, 231, 447, 448, 476 reactivity, 96, 97 structure, 96, 97 treatment of poisoning, 476–479 Carbaryl, 96 Carbendazim (Methyl benzimidazole-2-yl carbamate), 233, 237 chemistry, 237 mechanism of action, 238 toxicology, acute toxicity, 237 ecotoxicology, 238 human toxicology, 238 occupational toxicology, 238 primary irritation, 238 uses, 238 Carbofuran, 96 Carbon disulphide, 222, 279, 453 3-Carbonyl-5-ethoxy-1,2,4-thiadiazole, 253 Carboxanilide, 266 Carboxin (5,6-Dihydro-2-methyl-1,4-oxathi-ine3-carboxanilide), 195, 265, 266, 283, 289 chemistry, 266 mechanism of action, 265 toxicology, acute toxicity, 266 ecotoxicology, 267 human toxicology, 266 metabolism, 266 occupational toxicology, 266 primary irritation, 266 toxicokinetics, 266 uses, 266 538 INDEX 2-Carboxyethylmercapturic acid, 277 CAS see Chemical Abstracts Service CDC see Centers for Disease Control Centers for Disease Control, 366 Chemical Abstracts Service (CAS), Chitin synthesis inhibitors, 10, 174 Chlordecone, 61 absorption, 61, 62 experimental toxicology, 62 human toxicology, 63 mechanistic studies, 62, 63 metabolism, 61, 62 reproductive toxicology, 63 Chloroalkylthiodicarboximides, 242 5-Chloro-2-methyl-4-isothiazolin-3-one (CMIT), chemistry, 378 Chloroneb (1,4-Dichloro-2,5-dimethoxybenzene), 216 chemistry, 200 mechanism of action, 201 toxicology, acute toxicity, 201 primary irritation, 201 uses, 201 1-(4-Chlorophenoxy)-3,3-dimethyl-1-(1-H1,2,4-triazol-1-yl)butan-2-one see triademefon 1-(4-Chlorophenyl)-3-(2,6-difluorobenzoyl)urea see Diflubenzuron 1-(6-Chloro-3-pyridylmethyl)-N-nitroimidazolidin-2-ylideneamine see Imidacloprid Chlorothalonil (2,4,5,6-Tetrachloro-1,3benzenedicarbonitrile=Tetrachloroisophthalonitrile), 196 chemistry, 196 mechanism of action, 196 toxicology, acute toxicity, 197 chronic toxicity, 197 ecotoxicology, 197 human toxicology, 197 occupational toxicology, 197 oncogenicity, 197 primary irritation, 197 sensitizing potential, 197 uses, 196 Cholecalciferol, treatment of poisoning, 491 Cholinergic toxicity, 107, 108, 442, 447 treatment, 108–110 Chromosome damage, 13 Chronic toxicity, 11, 41, 132, 166, 169, 243, 385, 396, 397, 418, 504, 505, 517, 518 Cinnamic acid, 195, 274, 281 CMIT see 5-Chloro-2-methyl-4-isothiazolin-3-one Cocaine, 111 Colitis, 400 Common mechanism groups, 19 Coniothyrium minitans, 359–360 Consumer exposure, 425, 426 Cornea, opacity, 203, 212, 277 Cyanoacetamide, 369 Cyclodiene insecticides, absorption, 41 excretion, 41 human toxicity, 44 metabolism, 41, 42 mutagenesis, 43 neurotoxicity, 43, 44 production 39, 40 toxicity, 40, 41 uses, 39, 40 4-Cyclododecyl-2,6-dimethylmorphoine see dodemorph Cycloheximide (Acitidione=3-[2-(3,5Dimethyl-2-oxocyclohexyl)-2hydroxyethyl]glutarimide), 195, 280, 281, 284 chemistry, 280 mechanism of action, 280 toxicology, acute toxicity, 280 developmental toxicology, 281 genetic toxicology, 281 human toxicology, 281 uses, 281 INDEX Cyproconazole, chemistry, 249 mechanism of action, 249 toxicology, acute toxicity, 250 ecotoxicology, 250 human toxicology, 250 occupational toxicology, 250 primary irritation, 250 uses, 249 Cytogenetics, 13, 236, 276, 320, 382 DBNPA see 2,2-Dibromo-3-nitrilopropionamide DDAC see Di-n-Decyl-dimethyl ammonium chloride DDT see Dichlorodiphenyltrichloroethane Decontamination, 8, 473–475, 477, 481, 483, 485, 486, 489, 491 Delayed onset polyneuropathy, 13, 89, 108, 117, 442–444 Dermal dosimetry, Developmental toxicity, 9, 168, 173, 176, 178, 179, 242, 244, 310, 325, 398, 399, 518, 533 Dibromoacetamide, 369 2,2-Dibromo-3-nitrilopropionamide, 368–371 chemistry, 368 decomposition, 369 mechanism of action, 369 stability, 369 toxicology, acute toxicity, 369 developmental toxicity, 370 ecotoxicology, 371 genetic toxicology, 370 human toxicology, 370 primary irritation, 369 reproductive toxicology, 370 subchronic toxicology, 370 uses, 369 Dichloroacetic acid, 247 3,5-Dichloro-4-aminophenol, 202 1,4-Dichloro-2,5-dimethoxybenzene see chloroneb 539 Dichlorodiphenyltrichloroethane (DDT), 3, 27, 28, 48–55, 64 absorption, 48, 49 animal toxicity, 48 behavioral toxicity, 51 blood levels, 55 chronic effects, 53, 54 developmental neurotoxicity, 146, 147 distribution, 48, 49 fat levels, 55 human toxicology, 53, 54 metabolism, 49, 50 milk levels, 55 mutagenicity, 51, 52 neurotoxicity, 51 reproductive toxicology, 52 4,40 -Dichloro-2,20 -methylenediphenol see dichlorophen 2,6-Dichloro-4-nitro aniline see dicloran Dichlorophen (4,40 -Dichloro-2,20 -methylenediphenol), 216 chemistry, 216 mechanism of action, 216 toxicity, acute toxicity, 216 human toxicology, 216 occupational toxicology, 216 uses, 216 3,5-Dichlorophenol, 203 2,4-D see 2,4-Dichlorophenoxyacetic acid 2,4-Dichlorophenoxyacetic acid (2,4-D), 3, 326, 438, 441, 453, 456 chemistry, 324 reference dose, 325 toxicology, acute toxicity, 324, 325 absorption, 324 distribution, 324 excretion, 324 human toxicology, 325 metabolism, 324 2,6-Dichloro-p-phenylenediamine, 202 -(2,4-Dichlorophenyl)-1H-imidazole-1ethanol, 240 1,3-Dichloropropene, 456 skin effects, 456 human toxicology, 456 540 INDEX 1-(2,4-Dichloro-b-propylphenethyl)-1H-1, 2,4-triazole see penconazole O-2,6-Dichloro-p-tolyl o,o-dimethyl phosphorothiolate see Tolclofos-methyl Dicloran (2,6-Dichloro-4-nitro aniline), 201 chemistry, 201 mechanism of action, 202 toxicology, acute toxicity, 202 chronic toxicity, 202 developmental toxicity, 202 ecotoxicology, 203 human toxicology, 203 metabolism, 202 occupational toxicology, 203 oncogenicity, 202 reproductive toxicity, 202 toxicokinetics, 202 uses, 202 Di-n-decyl-dimethyl ammonium chloride chemistry, 373 toxicology, ecotoxicology, 374 sensitization, 374 Diet studies, Dietary risk assessment, 519 Diflubenzuron (1-(4-Chlorophenyl)-3(2,6-difluorobenzoyl)urea), 174 absorption, 174 acute toxicity, 175 carcinogenicity, 175 distribution, 174 excretion, 174 genetic toxicology, 176 human toxicology, 176 metabolism, 174, 175 reference dose, 176 reproductive toxicity, 175, 176 structure, 174 Dihydroazadirachtin, 183 genetic toxicology, 184 human toxicology, 184 reference dose, 185 toxicology, 183, 184 5,6-Dihydro-2-methyl-1,4-oxathi-ine-3carboxanilide see carboxin 5,6-Dihydro-2-methyl-1,4-oxathi-ine-3carboxanilide 4,4-dioxide see oxycarboxin Dimercaprol (BAL), 489 Dimercaptopropanesulfonate (DMPS), 489 Dimercaptosuccinic acid (DMSA), 489 Dimethomorph, chemistry, 281 mechanism of action, 282 toxicology, acute toxicity, 282 ecotoxicology, 282 human toxicology, 282 occupational toxicology, 282 primary irritation, 282 uses, 282 Dimethylamine, 223, 225 Dimethyldithiocarbamic acid, 220, 223, 225 3-[2-(3,5-Dimethyl-2-oxocyclohexyl)-2hydroxyethyl]glutarimide see cycloheximide Dimethyl-4,40 -(o-phenylene)bis(3-thioallophanate) see thiophanate-methyl Diniconazole, chemistry, 250 mechanism of action, 251 toxicology, acute toxicology, 251 ecotoxicology, 251 human toxicology, 251 metabolism, 251 occupational toxicology, 251 primary irritation, 251 toxicokinetics, 251 uses, 251 4,6-Dinitro-o-cresol (DNOC), human toxicology, 457 2,4-Dinitro-6-(2-octyl)phenol, 215 Dinocap, chemistry, 214 mechanism of action, 214 toxicology, acute toxicity, 214 chronic toxicity, 215 ecotoxicology, 215 INDEX human toxicology, 215 oncogenicity, 215 primary irritation, 215 sensitizing potential, 215 uses, 214 Diquat (1,10 -ethylene-2-20 bipyridyldiylium), chemistry, 319 reference dose, 320 structure, 306 toxicology, absorption, 319 distribution, 319 excretion, 319, 452 general toxicity, 320 genetic toxicology, 320 human toxicology, 320, 452 metabolism, 319 treatment of poisoning, 320, 485 Dithiocarbamates, 4, 13, 194, 217 DMPS see dimercaptopropanesulfonate DMSA see 2,3-Dimercaptosuuinic acid DNA damage, 13 DNOC see 4,6-Dinitro-o-cresol Dodemorph (4-Cyclododecyl-2,6-dimethylmorphoine), 261, 262 chemistry, 261 mechanism of action, 262 toxicology, acute toxicity, 262 ecotoxicology, 262 primary irritation, 262 uses, 262 Drinking water exposure, 523 Ecotoxicity, 193 Ecotoxicology, 16 Education, 14, 443, 449 EINECS see European Inventory of Existing Chemicals ELINCS see European List of Notified Chemicals Emetics, 11 Endocrine disruption, 524 Engineering controls, 14 541 Enilconazole see imazalil 5-Enoylshikimate 3-phosphate synthase, 10, 331 Environment, 1, 2, 14, 16, 18, 19, 27, 28, 47, 60, 186, 193, 197, 200, 203, 208, 213, 215, 219, 220, 223, 225, 227, 229, 230, 233, 235, 237, 238, 240–242, 244, 247, 248, 250, 253–258, 260–262, 264–269, 271, 272, 278, 279, 282, 294, 318, 356, 414, 502, 504, 506–509, 514–516, 527, 528, 534 Environmental Protection Agency (EPA), 19, 351, 365, 433, 447, 513, 528 EPA see Environmental Protection Agency Epidemiology, 9, 13, 355, 359 Ergosterol bisynthesis-inhibiting fungicide (EBIF), 249 Escherichia coli, 379 Ethyl 2-[(diethoxyphosphinothioxyl)oxyl]-5methylpyrazolol(1,5-a)pyramidine-6carboxylate see pyrazophos Ethyl 3-trichloromethyl-1,2,4-thiadiazol-5yl ether see etridazole Ethylan, toxicity, 56 Ethylene bisdithiocarbamates, 194, 217, 225 Ethylene-bisthiuram disulphide, 227 Ethylenediamine, 227 Ethylene oxide, 366 Ethylene thiourea (ETU), 227, 229 Ethylene thiuram disulphide, 229 Etridazole (Ethyl 3-trichloromethyl-1,2,4thiadiazol-5-yl ether), 252 chemistry, 252 mechanism of action, 252 toxicology, acute toxicity, 252 ecotoxicology, 253 human toxicology, 253 occupational toxicology, 253 primary irritancy, 252 toxicokinetics, 253 uses, 252 EU see European Union 542 INDEX European Inventory of Existing Chemicals, European List of Notified Chemicals, European Union (EU), 2, 3, 18, 64, 351, 418, 422, 432, 501, 502, 511 Eye, 15, 64, 170, 179, 182, 197, 199, 200, 206, 215, 220, 221, 224, 226, 228, 230, 232, 234, 236, 239, 243, 245, 248, 250, 251, 255, 258, 259, 262, 266, 268–270, 273, 277, 279, 282, 312, 352, 355, 356, 369, 370, 380, 387, 388, 393, 394, 400, 450, 453, 483, 485, 504, 518, 529, 533 Face shield, 15, 215 Federal Food, Drug and Cosmetic Act (FFDCA), 513 Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), 1, 18, 365, 513 Fenbuconazole, chemistry, 253 mechanism of action, 254 toxicology, acute toxicity, 254 ecotoxicology, 254 human toxicology, 254 occupational toxicology, 254 uses, 254 Fenpropiomorph, chemistry, 263 mechanism of action, 263 toxicology, acute toxicity, 263 ecotoxicology, 264 human toxicology, 264 occupational toxicology, 264 primary irritation, 263 uses, 263 Ferbam (Iron tris(dimethyldithiocarbamate)), 219 chemistry, 219 mechanism of action, 219 toxicology, acute toxicity, 220 human toxicology, 220 occupational toxicology, 220 primary irritation, 220 subchronic toxicology, 220 uses, 220 FFDCA see Federal Food, Drug and Cosmetic Act FIFRA see Federal insecticide, Fungicide and Rodenticide Act Fipronil, (5-amino[2,6-dichloro-4(trifluoromethyl)phenyl]-4-[(1R,S)-(trifluoromethyl)sulfinyl]-1H-carbonitrile), 169 absorption, 170 acute toxicity, 170 distribution, 170 excretion, 170 genetic toxicology metabolism, 170 reference dose, 172 reproductive toxicity, 171 structure, 169 Fluorescent tracer technique, Fluoroacetic acid, 454 poisoning, 454 Folpet (N-(Trichloromethylthio) phthalimide), 247 chemistry, 247 mechanism of action, 247 toxicology, acute toxicity, 248 ecotoxicology, 248 human toxicology, 248 metabolism, 248 occupational toxicology, 248 primary irritation, 248 toxicokinetics, 248 uses, 247 Food Quality Protection Act (FQPA), 18, 514 Formaldehyde, 366, 375, 384, 393 Formulation, 7, 10–12, 14, 16, 17, 48, 129, 140, 163, 176, 206, 207, 355, 356, 359, 373, 376, 379, 387, 433, 434, 449, 450, 453, 522 FQPA see Food Quality Protection Act Fuberidazole (2-(2-furyl)benzimidazole), 194, 231, 241, 285 chemistry, 241 mechanism of action, 241 INDEX toxicology, acute toxicity, 241 ecotoxicology, 242 human toxicology, 241 occupational toxicology, 241 primary irritation, 241 uses, 241 Fumigants, 454, 455 Fungi, 1–3, 10, 161, 195, 224, 195, 238, 269, 351, 360, 366, 373, 375, 376, 385, 386, 389, 531 Fungicides, antibiotic, 279–281 azoles, 248–261 benzimidazole, 231–242 carboxanilides, 265–268 categories, 193 characteristics, 193 chemical classes, 194 chloroalkylthiodicarboximides, 242–248 cinnamic acid class, 281, 282 classification, 193 complete listing, 282–292 curative, 193 dithiocarbamates, 217–225 dressing, 193 eradication, 193 ethylene bisdithiocarbamates, 225–231, 453 foliar, 193 halogenated substituted monocyclic aromatic, 196–217 metallic, inorganic, 272 miscellaneous, 274–278 morpholines, 261–265 oncogenic risk, 195 organometallic, 273, 274 organophosphate fungicides, 268–271 piperazines, 271, 272 protective, 193 soil application, 193 thiabendazole, 231–242 thiocarbonates, 278, 279 toxicology, 195 2-(2-furyl)benzimidazole see fuberidazole 543 GA see Glutaraldehyde GA see tabun GB see sarin Genetic toxicology, 11, 204, 207, 210, 236, 240, 244, 246, 275, 281, 370, 381, 385, 387, 397, 398 Glufosinate (4[hydroxy(methyl)phosphinoyl]-DL-alanine) chemistry, 333 reference dose, 333 structure, 333 toxicology, animal toxicity, 333 human toxicology, 334 treatment of poisoning, 485 Glutaraldehyde, 367, 388–401 chemistry, 388 decomposition, 389 mechanisms of action, 388, 389 stability, 389 toxicology, acute toxicity, 390–392 chronic toxicology, 396–398 developmental toxicology, 398, 399 ecotoxicology, 400, 401 genetic toxicology, 398 metabolism, 399, 400 occupational medicine, 400 oncogenicty, 396–398 peripheral sensory irritation, 394, 395 primary irritation, 392 reproductive toxicology, 398, 399 sensitization, 392 subchronic toxicology, 395, 396 toxicokinetics uses, 366, 389, 390 Glyphosate (N-Phosphonomethyl glycine), chemistry, 331 reference dose, 332 toxicology, animal toxicity, 331, 332 human toxicology, 332, 453 treatment of poisoning, 332, 485 Goggles, 15, 215, 370 544 INDEX Good agricultural practice, 414 Growth regulators, 1, 2, 4, 160, 174, 185, 334, 501 Haemoglobin, alkylation, Haemolytic anaemia, 178, 230 Halogenated aromatics, 203 Harmonization, 433, 511, 515, 517 Hazard identification, 517–519 Health and Safety Executive (HSE), 3, 14, 400, 477 Herbicides, 2, 3, 10, 305–334 bipyridylium, 305, 306 classification, 306 inorganic, 305 malignancy, 321–324 nitriles, 329 organophosphorus, 331 phenoxy acid, 320, 321, 481 substituted anilines, 327, 328 trazines/triazoles, 329 ureas/thioureas, 328, 329 Hexachlorobenzene (Perchlorobenzene HCB), 44, 203 chemistry, 203 mechanism of action, 204 toxicology, acute toxicity, 204 chronic toxicity, 204 developmental toxicity, 204 genetic toxicology, 204 human toxicology, 205 occupational toxicology, 205 oncogenicity, 204 reproductive toxicity, 205 uses, 204 Hexachlorocyclohexane, 3, 32–39 absorption animal toxicity, 33, 34 behavioural toxicity, 35–37 carcinogenicity, 37 distribution, 34 excretion, 34, 35 human toxicology, 38, 39 metabolism, 34, 35 mutagenicity, 37 neurotoxicity, 35–37 reproductive toxicology, 37, 38 uses, 366 Hexaconazole, chemistry, 255 mechanism of action, 255 toxicology, acute toxicity, 255 ecotoxicology, 256 human toxicology, 255 occupational, 255 primary irritation, 255 uses, 255 HSE see Health and Safety Executive 5-Hydroxy-2-aminobenzimidazole, 237 4-[Hydroxy(methyl)phosphinoyl]-DLalanine see Glufosinate 3-Hydroxypropylmercapturic acid, 277 4-Hydroxy-2,5,6-trichloroisophthalonitrile, 197 IARC see International Agency for Research on Carcinogenesis Imazalil (Enilconazole), 5, 194, 231, 239, 240, 249, 286, 437 chemistry, 239 mechanism of action, 239 toxicology, acute toxicity, 239 chronic toxicity, 240 developmental toxicity, 240 ecotoxicology, 240 genetic toxicology, 240 human toxicology, 240 occupational toxicology, 240 oncogenicity, 240 primary irritation, 239 reproductive toxicity, 240 uses, 239 Imidacloprid (1-(6-Chloro-3-pyridylmethyl)-N-nitroimidazolidin-2ylideneamine), 166 absorption, 167 acute toxicity, 168 distribution, 167 ... 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